Patent EA-003102-B1 (EA)
Title: Sulfonamide derivatives as inhibitors of bone resorption and inhibitors of cell adhesion, process for preparation thereof, use and pharmaceutical composition
Inventor: PEYMAN ANUSCHIRWAN
IPC: A61P9/10
Filed: 1999-01-16
Abstract: 1. A compound of the formula I   in which R<1> and R<2> together are a bivalent (C2-C3)-alkylene radical; R<4> is hydrogen or (C1-C6)-alkyl; R<5> is (C1-C10) alkyl, (C6-C14) aryl, (C5-C14)heteroaryl or (C6-C14)aryl (C1-C10) alkyl group, where the aryl radical, the heteroaryl radical, the alkyl radical are optionally substituted by R<3>, or 2-oxo-bicyclo [2.2.1]hepto-1-yl-methyl group; R<3> is (C1-C4)alkyl, (C1-C4)alkoxy, halogen, trifluoromethyl, cyano, oxo, NHCO-(C1-C4)alkyl or -C(O)NH-(C5-C14) heteroaryl radical or phenyl; R<6> is H; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 2. Compounds of the formula I as claimed in claim 1, in which R<5> is (C6-C14)aryl, (C5-C14)heteroaryl, where aryl or heteroaryl is optionally substituted by R<3>; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 3. Compounds of the formula I as claimed in claim 1, in which R<5>is a naphthyl in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts and their prodrugs. 4. Compounds of the formula I as claimed in one or more of claims 1 to 3, which is a 2-(R<5>-sulfonylamino)-3-(4-(2-( 1,4,5, 6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)-benzoylamino) propionic acid wherein the 2-(R<5>-sulfonylamino) substituent is selected from the group consisting of benzenesulfonylamino, 4-(n-propyl)benzenesulfonylamino, 4-tert-butylbenzenesulfonylamino, 2,4,6trimethylbenzenesulfonylamino, 4-methoxybenzenesulfonylamino, 4-(n-butoxy)benzenesulfonylamino, 3-chlorobenzenesulfonylamino, 4-chlorobenzenesulfonylamino, 3-trifluoromethylbenzenesulfonylamino, 4-trifluoromethylbenzenesulfonylamino, 4-acetylaminobenzenesulfonylamino, 2-cyanobenzenesulfonylamino, naphthalene-1-sulfonylamino, naphthalene-2-sulfonylamino, biphenyl-4-sulfonylamino, thiophene-2-sulfonylamino, quinoline 8-sulfonylamino, methanesulfonylamino, propane-1-sulfonylamino, propane-2-sulfonylamino, butane-1-sulfonylamino, 2-methylpropane-1-sulfonylamino, chloromethanesulfonylamino, 2,2,2-trifluoroethanesulfonylamino, 7,7-dimethyl-2-oxo-bicyclo(2.2. 1 ]hept-1-ylmethanesulfonylamino and 2-phenylethenesulfonylamino in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts and its prodrugs. 5. A compound of the formula I as claimed in one or more of claims 1 to 4, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2- ylcarbamoyl)-ethyl)benzoylamino)propionic acid and its physiologically tolerable salts and its prodrugs. 6. A compound of the formula I as claimed in one or more of claims 1 to 5, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4, 5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)benzoylamino)propionic acid or a (C1-C4)-alkyl ester thereof, and its physiologically tolerable salts. 7. A compound of the formula I as claimed in one or more of claims 1 to 6, which is (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6- tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)benzoylamino)propionic acid ethyl ester, and its physiologically tolerable salts. 8. A process for the preparation of a compound of the formula I as claimed in claims 1 to 7, which comprises linking two or more fragments which can be derived retrosynthetically from the formula I, wherein a carboxylic acid or a carboxylic acid derivative of the formula II:   in which R<4> and R5 are defined as indicated in claims 1 to 7, or alternatively functional groups are present in the form of precursors or in protected form, and X is a nucleophilically substitutable leaving group, is reacted with a guanidine or guanidine derivative of the formula Ill:   in which R<1>, R<2> and R<6> are defined as indicated in claims 1 to 7, or alternatively functional groups are present in the form of precursors or in protected form. 9. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs as an active ingredient for use as a pharmaceutical. 10. A pharmaceutical preparation, comprising at least one compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs in addition to a pharmaceutically innocuous carrier. 11. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as a vitronectin receptor antagonist. 12. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of bone resorption or for the therapy or prophylaxis of osteoporosis. 13. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of tumor growth or tumor metastasis. 14. A compound of the formula I as claimed in one or more of claims 1 to 7 and/or its physiologically tolerable salts and/or its prodrugs for use as anti inflammatory or for the therapy or prophylaxis of cardiovascular disorders, restenosis, arteriosclerosis or retinopathies.